Monthly mini-dose rituximab for primary anti-PLA2R-positive membranous nephropathy: a personalized approach

Our study shows that monthly mini-dose rituximab monotherapy was successful in treating PLA2R-associated PMN. The NS remission rate after eighteen months was 84% at an average dose of rituximab 820 mg (range, 300–1800 mg). Clinical remission rates were similar in both groups, but the anti-PLA2R high-titer group required more cumulative doses of rituximab than the low-titer group.

Rapid and long-lasting B-cell depletion is essential to achieve a good therapeutic effect with B cell-targeting treatments. We set out to investigate whether rituximab 100 mg could achieve rapid B-cell depletion. Our data show that a single dose of rituximab 100 mg could achieve B-cell depletion in 87% of individuals, and that such depletion could be maintained for at least one month. We speculated that the rationale underlying this observation was as follows. First, the B-cell count in peripheral blood was within the normal range in patients with PMN. Therefore, a lower dose of rituximab was needed to achieve B-cell exhaustion compared to lymphoma. Ramachandran et al. also achieved CD19 depletion with a single dose of rituximab 100 mg [13]. Literature confirmed CD19 + B-cell depletion occurs fast (within few hours) and almost all patients achieve it, even after receiving small doses [14]. Therefore, a “CD19-targeted therapy” has been proposed to avoid unnecessary additional infusions and prevent relapses when needed [14].

Long-lasting B-cell depletion is beneficial for the negative conversion of anti-PLA2R antibodies, and can be accomplished by a regular dose of rituximab with a high peak, resulting in a strong depletion of B cells initially, followed by a gradual decline [15]. However, we adopted a different approach by administering rituximab monthly. Seitz-Polski et al. compared the NICE and GEMRITUX studies and found that the initial frequency of rituximab administration and remission rate were higher in the former (1 g on days 1 and 15). They found that the residual rituximab level after 3 months was greater in the NICE cohort than that in the GEMRITUX cohort, which is an important factor impacting the choice of dosing regimen. Three months after administration, the serum rituximab concentration was measurable in about half of the patients in the NICE study, but undetectable in almost all patients in the GEMRITUX study (rituximab 375/m2on days 1 and 8) [16]. Our regimen of monthly administration of rituximab 100 mg guaranteed a more effective rituximab concentration compared to the expected residual rituximab level at 3 months.

We think that a lower degree of loss via urine was probably another advantage of our mini-dose rituximab regimen. The pharmacokinetics of rituximab in PMN is unknown; some studies report that it differs substantially from that of follicular lymphoma and other autoimmune diseases [15, 17]. The half-life of rituximab is shorter in PMN (approximately 11.5 days) than in lymphoma (approximately 20 days) [15], probably because of the gross loss in urine [18]. Rituximab has been shown to be detectable in the urine of patients with PMN. This loss via urine caused the residual rituximab levels at month 3 to be significantly lower in PMN patients compared to myasthenia gravis patients with no proteinuria (matched for age, gender, and weight, and treated with a similar treatment regimen) [17]. Although we did not detect rituximab lost in the urine, based on the above literature there is reason to speculate that the standard rituximab protocol would have resulted in more loss via urine during the gross proteinuria period, whereas our mini-dose rituximab regimen resulted in less loss, which declined even further in the following months because of the amelioration of proteinuria.

The minimum effective dose of rituximab required for B-cell depletion is not currently known with precision, but it warrants discussion. Considering the peak concentration observed in our study, we speculated that rituximab 20 + µg/mL approximated the minimum effective serum concentration. There is some evidence to support this speculation. First, it was demonstrated to be effective in our study. Second, Iijima et al. reported that almost no recurrence occurred after 3 months with an average serum rituximab concentration of 28.8 µg/mL in steroid-resistant children with nephrotic syndrome (minimal change disease or focal segmental glomerulosclerosis) [19]. Third, the residual concentration of rituximab (approximately 20 + µg/mL) at three months contributed to the higher remission rate in the NICE cohort compared to undetectable residual rituximab at three months with a lower remission rate in the GEMRITUX study [16]. These data strengthen our claim that rituximab 20 + µg/mL is an effective serum concentration, and may approximate the minimal effective dose of rituximab.

We were unsure about the suitable interval for next dose after the initial administration of rituximab 100 mg. Based on the monthly cyclophosphamide experience, we administered rituximab 100 mg at monthly intervals. One month after rituximab 100 mg administration, the average trough rituximab concentration was 1.0 µg/mL, and the B cells were still in a state of exhaustion. We deliberated whether an additional dose of rituximab should be given at that time, or if it was more appropriate to wait for B-cell replenishment. We could not find any study that utilized a similar rituximab concentration in patients with PMN, although one study that investigated minimal change disease reported that the rate of recurrence at 3 months was significant when the average rituximab concentration was 2.3 µg/mL [19]. Thus, we thought that the trough concentration of rituximab in our study was not effective and that supplementation was necessary, despite the persistence of B-cell exhaustion. If the pathogenic factors causing PMN persist, B-cell regeneration may lead to a resurgence or elevation in anti-PLA2R antibodies, which would be remedied by monthly rituximab supplementation. Although the metabolism of rituximab in patients with PMN is incompletely understood, a monthly intermittent mini-dose regimen could maintain the rituximab concentration between the peak-to-trough fluctuations; moreover, continuous B-cell depletion was observed, which blocked anti-PLA2R antibody production, eventually achieving an immunological target response of ≤ 2 RU/mL.

The NS remission rate with the mini-dose rituximab regimen was non-inferior to the regular rituximab strategy. Our remission rate was 46.9% with a 6.3% CR rate at six months, which is not inferior to the results of previous studies. The six-month remission rates in the renowned randomized controlled trials (RCTs) were as follows: 35% in the GEMRITUX study [4], 35% in the MENTOR study [5], 44% in the STARMEN study [6], and 51% in the RI-CYCLO study [7]. Our remission rate was 78% with 25% CR at twelve months (average cumulative dose of rituximab 750 mg), which was also non-inferior to the results of previous studies. The twelve-month remission rates were 60% in the Mentor study [5], 51% in the STARMEN study [6], and 62% in the RI-CYCLO study [7]. Ramachandran et al. reported 50% remission in six patients with PLA2R-related refractory PMN with 2–4 doses of rituximab 100 mg at six months, [13] which bore close resemblance to our results.

Single or multiple infusion strategies for rituximab 100 mg, which yielded positive results, have been reported for other autoimmune diseases, including ABO-incompatible living-donor kidney transplantation [20], de novo donor-specific anti-HLA antibody-associated renal transplantation [21], steroid-dependent minimal change NS [22], and steroid-refractory thrombocytopenia due to systemic lupus erythematous [23], Our treatment course was relatively flexible and included cumulative doses and dosing intervals. The cumulative doses varied individually according to the anti-PLA2R levels and remission. In fact, the high anti-PLA2R group required higher cumulative rituximab doses and longer treatment durations. The dosing intervals were not very strict; a delay or advance of one or two weeks was acceptable. There was a gap of up to 2–3 months in the treatment regimens of some patients due to the COVID-19 epidemic and control measures in China, visible/potential infection, or other events that were deemed more important than PMN.

A progressive decline in serum anti-PLA2R antibodies after two doses of rituximab was observed in most individuals in our study. Since well-differentiated plasma cells may continue producing anti-PLA2R antibodies, the serum anti-PLA2R antibody levels may continue to rise even after the first rituximab dose, and decrease only upon exhaustion of the existing plasma cells. This steady decline was indicative of the onset of the effect of rituximab. As long as the B cells were in a state of depletion, the decline in the anti-PLA2R antibody levels was sustained. The rate of decline of the anti-PLA2R antibodies was similar; thus, the low-titer group was more likely to reach the target of ˂ 2 RU/mL than the high-titer group, which means that a higher dose of rituximab would be needed in the latter.

Recurrence is a concern because of the small total amount of rituximab administered in our study. However, the median follow-up duration was 24 months (range, 18–38), and two recurrences were observed. The relapse rate in the rituximab group in the STARMEN trial was 7% (3/43), and that in the RI-CYCLO study was 8% (3/37), which were very similar to our cohort. This may be attributed to frequent administration and longer total effective rituximab period.

Rituximab is a B cell-targeted therapy. It has already been recommended as first-line treatment for PMN by the 2021 KDIGO guidelines [2]. The guidelines recommend two standard treatment regimens for rituximab; however, clinically, there is controversy regarding the specific dosage and interval. Fenoglio et al. reported that the effects of rituximab 375 mg/m2administered once and four times were the same when treating PMN [24]. We believe that the specific dosing regimen should be adjusted according to the patient’s age, primary disease, comorbidities, and immune status. Mini-dose rituximab may be more suitable for the “vulnerable” subset of the PMN population (such as the elderly, patients susceptible to infection, those who have newly recovered from a severe infection, or patients with very low serum immunoglobulin, and low anti-PLA2R antibody titer). The regimen should not be adopted in PMN patients with high anti-PLA2R titer. The KDIGO guidelines consider an anti-PLA2R antibody > 50 RU/mL to be among the additional conditions for high risk of recurrence. Previous studies have shown that patients with high titers of PLA2R antibodies have low rates of spontaneous remission [25]. Therefore, we inferred that patients of PMN with high titers of anti-PLA2R antibodies treated with optimal supportive care and observation for 6 months are not optimal candidates for the mini-dose regimen. Immediate initiation of immunosuppressive therapy in conjunction with maximal supportive care is a rational regimen if clinicians consider the patient to be at a high or very high risk of progression to ESRD. From the perspective of health economics, rituximab is not covered by medical insurance in China. We achieved a non-inferior response rate compared to standard therapy using approximately one-fourth the conventional dose, which also reduced the medical cost. Our mini-dose, frequent-administration regimen makes rituximab affordable for patients with limited financial resources.

We were also concerned that continuous maintenance of B-cell depletion may affect normal immunoglobulin expression and lead to persistent humoral immune dysfunction [9, 10]. However, our data showed that immunoglobulin G levels at six and twelve months were significantly higher than those at baseline. Moreover, serum immunoglobulin G levels in the remission group were significantly higher than those in the non-remission group at six and twelve months, which suggested that the faster the remission of NS, the earlier the recovery of humoral immune function. A total of eight episodes of infections occurred in six patients in our cohort (19%), all of whom recovered rapidly. This is comparable with other previously published papers on rituximab therapy in MN. The infection rates were 28% in the Mentor study [5], 3% in the GEMRITUX Study [4], 30% in the STARMEN study [6], and 14% in the RI-CYCLO study [7].

Another potential concern is the development of anti-rituximab antibodies with this mini-dose repeated regimen. Patients with autoimmune disorders exhibit greater risk of anti-rituximab antibody development and anti-rituximab antibody-related adverse events [26]. Since the efficacy and safety of our mini-dose monthly therapy was similar to that of standard care, we did not check whether patients developed antibodies against rituximab or not.

Our study has some limitations. This real-world retrospective observational study was conducted at a single center with a small sample size. Another limitation was that only 10 of the 32 patients used the maximum tolerable dose of RASI for more than 6 months before starting rituximab therapy. According to KDIGO guidelines, there is a 20–45% chance of spontaneous remission in membranous nephropathy, and consequently, starting immunosuppressive therapy before 6 months of conservative therapy might overestimate the response rate to therapy [2]. Further multicenter RCTs comparing low-dose rituximab with standard doses of rituximab are needed to confirm the efficacy and safety of this strategy.

In summary, our data suggest that monthly rituximab 100 mg appeared as a potential effective regimen for treating anti-PLA2R-associated primary membranous nephropathy with a low anti-PLA2R titer, especially suitable for a certain subset of patients, such as the elderly, those susceptible to infection, and patients with limited financial resources. However, this regimen should not be adopted in PMN patients with high anti-PLA2R titer.

留言 (0)

沒有登入
gif